The stem-cell niche as an entity of action

NATURE|Vol 441|29 June 2006|doi:10.1038/nature04957                                                                                                   INSIGHT REVIEW




The stem-cell niche as an entity of action
David T. Scadden1

Stem-cell populations are established in ‘niches’ — specific anatomic locations that regulate how they
participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion,
while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue
physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms.
Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The
interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and
for the ultimate design of stem-cell therapeutics.

In architecture, the word niche refers to a recess, and in ecology it refers                and Caenorhabditis elegans, the germ stem cells reside at the distal end
to a habitat where an organism can reside and reproduce; in French, it                      of a tapered structure, and have been shown to depend upon interac-
refers to a dog-house. So, the grand position of the stem cell in popular                   tions with somatic cells at the end of that structure to maintain stem-cell
concepts of science is appropriately humbled by the cells dwelling in                       features2–4. The notion that heterologous cell types compose the niche
a place where they might awaken with fleas. However, the niche does                         was well supported by this early work and has led to emphasis on defin-
provide both conceptual and physical depth to the stem cell. Stem cells                     ing similar cell-based niche components in mammalian tissues. This
are, after all, defined by their function in complex multidimensional                       has yielded identification of the osteoblast in the bone marrow, and the
environments over time. Stem cells are by themselves of limited inter-                      endothelium in the brain, and possibly in the bone marrow5–8. Whether
est, but the integration of stem cells and their descendents into tissues                   there is a necessity for another cell type — other than the stem cell — to
is the basis for higher forms of life. Therefore, the niche is as critical as               be present for a niche to function, however, has recently been brought
stem-cell-autonomous functions in shaping our understanding of basic                        into question.
stem-cell biology, and how it contributes to health and disease.                               Two reports have demonstrated that the posterior mid-gut popula-
   Although a place of residence would fulfil the architectural concep-                     tions of cells in Drosophila have the capacity to produce daughter cells of
tion of the niche, it is inadequate in regard to stem cells. The niche in                   at least two types: enterocytes and enteroendocrine cells9,10. These cells
cell biology is more appropriately considered along ecologic lines, and                     seem to be able to self-renew and provide a long-lived ability to gener-
requires a sustaining function. The simple location of stem cells is not                    ate more mature offspring in a clonal manner. Notably, however, these
sufficient to define a niche. The niche must have both anatomic and                         cells do not appear to be in direct contact with a heterologous cell type.
functional dimensions, specifically enabling stem cells to reproduce                        They do have focal localization of the β-catenin paralogue, Armadillo,
or self-renew. This becomes particularly important as new sites of                          at the interface between the stem cell and its descendant daughter cell
stem-cell localization are defined.                                                         (the enteroblast), but this is distinct from the cells of different lineages
   Adult or somatic stem cells generally have limited function without                      composing most previously defined niches. The stem cells in this case sit
the niche. A case in point is the haematopoietic stem (HS) cell, which                      on a basement membrane that divides them from surrounding muscle
regenerates the entire blood and immune system, and makes copies of                         cells. It is suggested that the basement membrane itself might participate
itself after limit-dilution transplantation. HS cells circulate freely, but                 in the specialized microenvironment, possibly providing an opportunity
seem to have little function outside specific anatomic locations. It is                     for shifting location of the stem cell, sliding along a continuum of the
specific cues from specific sites that allow stem cells to persist, and to                  intestine. These data challenge the expectation that heterologous cells
change in number and fate. Importantly, it is also the niche that pro-                      must necessarily be within the niche, and suggest that some stem cells
vides the modulation in stem-cell function needed under conditions                          might have a niche composed of extracellular matrix and other non-cel-
of physiologic challenge. It is this dynamic capability that makes the                      lular constituents that could regulate their control (Fig. 1).
‘niche’ concept particularly important and central to the realization                          The concept of extracellular matrix regulating primitive cells is long-
of regenerative medicine. It is the ability of the niche to impose func-                    standing and at least three examples now exist in mammalian stem-cell
tions on stem cells that makes the concept important in disease. We                         systems. The first is in the skin, where β-1 integrins are known to be dif-
are now at a time when descriptive studies are giving way to those                          ferentially expressed on primitive cells and to participate in constrained
of physiology. This review attempts to integrate the issues of niche                        localization of a stem-cell population through presumed interaction
components, signals and modification, and determinism imposed by                            with matrix glycoprotein ligands11,12. Second, in the nervous system,
the niche to portray the dynamism inherent in niche biology.                                absence of tenascin C alters neural stem-cell number and function in
                                                                                            the subventricular zone13. Tenascin C seems to modulate stem-cell
Niche elements reconsidered: the role of extracellular matrix                               sensitivity to fibroblast growth factor 2 (FGF2) and bone morphoge-
The concept of a niche as a specialized microenvironment housing stem                       netic protein 4 (BMP4), resulting in increased stem-cell propensity
cells was first proposed by Schofield almost 30 years ago in reference to                   to generate glial offspring. In the haematopoietic system, tenascin
mammalian haematology1, although experimental evidence was first pro-                       C deletion has also been shown to affect primitive cell populations,
vided by invertebrate models. In the gonads of Drosophila melanogaster                      raising the possibility that it participates in several stem-cell niches14.
1
Massachusetts General Hospital Center for Regenerative Medicine, Harvard Stem Cell Institute, 185 Cambridge Street, CPZN – 4265A, Boston, Massachusetts 02114, USA.

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                                                                                   HH family members have a role in topographic organization and for-
              a
                                                                                mation of niches in development. Sonic hedgehog (SHH) is essential for
                                                                                hair-follicle formation, and distinguishes the localization of specific sub-
                                                                                sets of epidermal stem cells to either the follicular niche or the interfol-
                                                                                licular epidermis28,29. In addition, SHH participates in specific spatially
                                                                                restricted events within established niches. Hair represents a uniquely
                                                                                dynamic physical association of elements within a niche, owing to the
                                                                                change in distance during the hair cycle of the dermal papilla from the
                                                                                bulge region where at least some stem cells reside. Expression of SHH
                                                                                is spatially and temporally restricted, and seems to modulate new hair
                                                                                formation30, which is a function amenable to small-molecule manipula-
              b
                                                                                tion31. In the developing intestine, SHH and Indian hedgehog contribute
                                                                                to architectural patterning, playing a key part in assembly, dimensions
                                                                                and regularity of the crypts where stem cells reside32. Therefore, HH
                                                                                contributions to stem-cell control are morphogenic, creating a niche,
                                                                                and regulating stem-cell fate within that niche.
                                                                                   Maintaining physical organization of the established niche is prob-
                                                                                ably an active and important process; however, the signals governing it
                                                                                are not well defined. Indirect evidence suggests that ephrins, important
                                                                                mediators of structural boundaries in neural and vascular tissue, might
                                                                                participate in at least one stem-cell system. Graduated expression of
Figure 1 | Refining elements necessary for an adult stem-cell niche. a, Early
                                                                                ephrin B1 and, reciprocally, its transmembrane tyrosine kinase recep-
studies provided evidence that heterologous cell types created a three-
dimensional structure in which stem cells reside. b, Recent data raises the     tors, EphB2 and EphB3, has been elegantly shown to organize mouse
possibility that a regulatory microenvironment might include stem cells         intestinal epithelial cells33. Disrupted expression of the receptors leads
simply resident on the basement membrane with homologous cell–cell              to aberrant organization of crypt and villus cells, including cells at the
interactions. Stem cells are shown in deep green and more mature offspring      interposition between them, which are defined as stem cells. The altered
are represented by a lighter shade.                                             topographic orientation of primitive and maturing cells results in poly-
                                                                                ploid outgrowths. Therefore, it will be important to discern molecular
Third, another matrix protein, the Arg–Gly–Asp (RGD)-contain-                   events sustaining architectural organization of the niche, particularly
ing sialoprotein, osteopontin (OPN), has now been demonstrated to               in considering how niche elements might participate in dysregulated
contribute to HS-cell regulation15,16. Implicated previously in tumour          growth in tumours.
metastasis and cell-mediated immunity17,18, OPN interacts with several
receptors known to be on HS cells, CD44, and α4 and α5β1 integrins19,20.        Metabolism as an underexplored variable
It is produced by multiple cell types, among them osteoblasts that              Cells, matrix glycoproteins and the three-dimensional spaces they
contribute to the HS-cell niche. Notably, OPN production can vary               form provide ultrastructure for a stem-cell niche. The contact between
markedly, particularly with osteoblast activation. Animals deficient            these elements allows molecular interactions that are critical for regu-
in OPN have an increased HS-cell number, owing to a mechanism                   lating stem-cell function. Secreted proteins offer a paracrine measure
that is still debated but is microenvironment dependent15,16. Without           of control, but non-protein components of the local microenviron-
OPN, superphysiologic stem-cell expansion occurred under stimula-               ment also affect stem-cell function. One such participant was exam-
tory conditions15. Therefore, OPN seems to serve as a constraint on             ined for the haematopoietic niche based on the unusual mineral
HS-cell number, limiting the number of stem cells under homeostatic             composition of the bone adjacent to which at least a portion of the
conditions or with stimulation. Taking these three scenarios together,          stem cells reside. It was proposed that because the endosteal surface
matrix components provide localizing niche elements that can contrib-           is the location of bone remodelling, and osteoblasts and osteoclasts
ute stimulatory, or impose inhibitory, influences on the stem-cell pool.        are often co-localized, the known high ionic calcium concentrations
They, like other stimuli in the niche, balance opposing possibilities.          that exist near active osteoclasts might influence stem-cell function.
                                                                                Osteoblasts express receptor-activator of nuclear factor-B ligand
Paracrine factors and niche structure                                           (RANKL), which is essential for osteoclast differentiation and, thus,
Cells and extracellular-matrix components in the stem-cell niche are            the proximity of osteoblasts and osteoclasts. At the site of active bone
relatively predictable, although the complexity and integration of these        remodelling, ionic concentrations have been observed that dramati-
elements is far from understood. Soluble mediators of cellular response         cally exceed serum levels and vary with osteoclast activity. Cells sense
would also be expected and a number have been defined that are impor-           extracellular ionic calcium through the seven membrane-spanning
tant paracrine regulators of stem-cell function. Within the Drosophila          calcium-sensing receptor (CaR). This G-protein-coupled receptor
testis, Unpaired (UPD) is secreted by niche (hub) cells and induces             was found to be expressed on a stem-cell-enriched population of
stem-cell self-renewal via Janus kinase (JAK)–signal transducer and             bone-marrow haematopoietic cells, as well as select subsets of mature
activator of transcription (STAT) signalling21,22. In the Drosophila ovary,     haematopoietic cells34. Stem cells from mice genetically engineered
Decapentaplegic (DPP) is secreted after proteolytic cleavage and, along         to be CaR deficient had a markedly abnormal ability to engraft the
with another BMP analogue, Glass bottom boat (GBB), is produced by              bone marrow. They were functionally normal in the fetal liver and
niche (cap) cells23,24. These stimulate SMAD signalling in the germ stem        spleen, but were unable to engage with or be retained at the endosteal
cells and result in suppression of differentiation, maintaining the self-       niche. Simple molecules, including inorganic ions, might contribute
renewing stem-cell state25. Wingless-related proteins (WNTs) and their          to niche function.
antagonists, soluble Notch modulators, FGFs and Hedgehog (HH) also                 Metabolic products, such as calcium, which influence stem-cell
contribute input in a paracrine manner with varying capacity to induce          behaviour in the niche are likely to represent a dimension of stem-
proliferation or impair differentiation. HH, however, has an additional         cell control that allows cells to respond to varying conditions of tissue
intriguing function: it is secreted by cap cells and mediates proliferative     state. For example, oxidative stress markedly affects stem-cell func-
effects not just on germ stem cells, but also on surrounding somatic cells      tion. Under conditions in which ‘ataxia telangiectasia mutated’ (ATM)
composing the niche itself in the Drosophila ovary26,27. This effect on         deficiency was induced, reactive oxygen species (ROS) accumulated
niche composition is a common theme of HH extending to mammals.                 in HS cells in the bone marrow35. This was associated with increased
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NATURE|Vol 441|29 June 2006                                                                                                               INSIGHT REVIEW


levels of the cyclin-dependent kinase inhibitor associated with senes-                                  Humoral
cence, p16INK4a, and with evidence of markedly decreased stem-cell
function. Modifying ROS with anti-oxidants reduced p16INK4a and
rescued stem-cell function. Challenges of oxidative stress are therefore
                                                                                                        Structural
likely to be important in altering stem-cell fate. The changing local
                                                                                                                                                    Metabolic
metabolic conditions reflecting tissue state might thereby provide real-
time information to modulate stem-cell function. Metabolic sensing is                                                                                  Physical
a likely mechanism by which stem cells gauge the ‘needs’ of a tissue or
organism (Fig. 2). This requires further detailed anaylsis.

What changes in a niche?
                                                                                                        Paracrine                                      Neural
Experimental examination of systemic inputs to the niche might include
measuring stem-cell number or proliferation. However, the haemat-
opoietic system provides an additional feature, stem-cell trafficking,
which can be readily quantitated, making it attractive as an experi-
mental model. Stem-cell entry and exit from the niche are important
components of haematopoietic niche function that are essential in
development and persist in the adult.                                                    Figure 3 | Inputs feeding back on stem-cell function in the niche. Elements
                                                                                         of the local environment that participate in regulating the system of a
   Blood formation in early development occurs in distinct extra-embry-
                                                                                         stem cell in its tissue state are depicted. These include the constraints
onic and embryonic sites. The yolk sac, aorto-gonadomesonephros                          of the architectural space, physical engagement of the cell membrane
(AGM), placenta and fetal liver participate in embryonic and definitive                  with tethering molecules on neighbouring cells or surfaces, signalling
haematopoiesis in temporal sequence. Early haematopoietic-cell pro-                      interactions at the interface of stem cells and niche or descendent cells,
duction occurs with apparent independence in the yolk sac and AGM                        paracrine and endocrine signals from local or distant sources, neural input
regions. When the fetal liver becomes a source of blood-cell production,                 and metabolic products of tissue activity.
this is thought to occur by virtue of cells migrating from the AGM or
placenta. Similarly, as haematopoiesis transitions to the bone marrow,                   interleukin-8 (IL-8). The kinetics of mobilization by these factors varies
migration rather than de novo generation is thought to be critical. This                 markedly, reflecting differing mechanisms; however, one mechanism
is best exemplified by mice made genetically deficient in CaR, or in the                 not appreciated until recently is the ability of G-CSF to modify niche
chemokine CXCL12 or its cognate receptor CXCR4, which have normal                        cells. G-CSF is capable of altering osteoblast activity sufficiently to
production of fetal liver HS cells, but fail to transition to haematopoiesis             reduce production of CXCL12, despite the absence of G-CSF recep-
in the marrow space34,36,37. These phenotypes are due to HS cells failing                tors on these cells38. It was an elegant, if serendipitous, discovery that
to move to the marrow niche.                                                             mice with altered sympathetic nervous system function lack the ability
   The migratory nature of HS cells is therefore fundamental to their                    to mobilize stem cells from the bone marrow in response to G-CSF39.
developmental programme and remains ongoing in adulthood. HS cells                       Sympathetic nervous system input, whether induced by G-CSF or by
are found in the blood even under homeostatic conditions in mice                         neural agonists, modulates the niche sufficiently to change the localiza-
and, from what can be estimated on the basis of imperfect measures,                      tion of stem cells. As the nervous system is inherently a circuit capable
also in humans. These numbers can be dramatically modified on the                        of connecting anatomically disparate tissues, these studies indicate one
basis of stimulation by several cytokines, including granulocyte colony-                 potential means by which the stem cell might be able to ‘sense’ changes
stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF and                          in the state of the tissue or the organism. If there are changes, such as
                                                                                         distant injury, neural connections might mediate the response even at
                                                                                         the stem-cell level.
                                                                                            Besides the nervous system, an obvious ready means of connect-
                                    Osteopontin
                             (M. musculus bone marrow)
                                                                                         ing localized sites with information from a distance is the circulatory
                                                                                         system (Fig. 3). HS cells might directly exploit their frequent blood
                                    Tenacin C
                                (M. musculus brain)                                      trafficking to ‘survey’ input at a distance and some other stem-cell
                               Basement membrane
                                                                                         types might do the same40–42. More likely is the physical association of
                             (D. melanogaster intestine)                                 stem cells with the microvasculature. In development, the co-locali-
        Niche cell                                                  Stem cell            zation of endothelial cells and progenitor populations from tissues
                                      Matrix
          Hub cell                                               Germ stem cell          as diverse as pancreas, heart, brain, liver, adrenal, bone and blood
  (D. melanogaster testis)                                   (D. melanogaster testis)    reflect the potential for regulatory signals generated by endothelium
          Cap cell                                               Germ stem cell          or nascent vasculature to affect primitive cell fate (reviewed in ref. 43).
  (D. melanogaster ovary)                                    (D. melanogaster ovary)
                                                                                         The adult hippocampus continues to generate neurons from precur-
       Distal tip cell                                          Germ stem cell
     (C. elegans gonad)                                        (C. elegans gonad)
                                                                                         sor populations in perivascular loci that contain proliferating neural
       Osteoblast                                           Haematopoietic stem cell
                                                                                         precursors, angioblasts and glial cells7. This region has been called
(M. musculus bone marrow)                                  (M. musculus bone marrow)     an ‘angiogenic niche’. Similarly, HS cells have been observed in abun-
      Endothelial cell                                         Neural stem cell          dance in close physical association with bone-marrow microvessels
    (M. musculus brain)             Extracellular             (M. musculus brain)        using recently defined immunohistochemical reagents8. The sites on
                                   (non-protein)                                         such vessels where primitive cells engage and diapedese seem to be
                                Oxidative state, Ca2+                                    highly discontinuous, and are functionally distinguished by abundant
                             (M. musculus bone marrow)                                   CXCL12 and E-selectin expression44. Although cells seem to reside
                                                                                         there, only indirect data suggest that this represents a location that is
                                                                                         regulating stem-cell function rather than just serving as a way-station
Figure 2 | Elements identified in stem-cell niches from various organisms
and tissues. Intentionally excluded are the complex molecular                            for highly mobile cells. It is likely that the perivascular site is indeed a
interactions that are present at the interface between the stem cell and its             niche; however, at present, the data on function that are necessary to
niche cell counterpart. These are reviewed extensively elsewhere54,55.                   confirm this conclusion are lacking for stem cells. The haematopoietic
C. elegans, Caenorhabditis elegans; D. melanogaster, Drosophila                          cells known to be regulated in association with marrow vessels are
melanogaster; M. musculus, Mus musculus.                                                 committed progenitors45.
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             a                                                                     What can a niche change?
                                                                                   The variability in niche number and function implicitly raises the
                                                                                   issue of whether such modifications can participate in disease states
                                                                                   or be induced to achieve therapeutic outcomes. Although altering
                                                                                   normal stem-cell function is clearly one potential effect of altered
                                                                                   niche dynamics, another more ominous possibility has been raised
                                                                                   by lessons learned in Drosophila. Experimentally-induced stem-
                                                                                   cell vacancy in the ovarian germ stem-cell niche did not result in
                                                                                   immediate loss of niche structural integrity or potential. Rather, the
                                                                                   empty niche could be occupied by somatic cells and, if not termi-
             b                                                                     nally differentiated, ectopic proliferation could ensue51. Furthermore,
                                                                                   altered expression of a niche product, such as DPP, could induce
                                                                                   more mature progenitor populations (cystocytes in Drosophila) to
                                                                                   revert to a stem-cell phenotype52. A stem-cell state could be imposed
                                                                                   upon more mature cells. Although neither of these scenarios has been
                                                                                   explored in vertebrate systems, these mechanisms could be predicted
                                                                                   to result in niche-generated disease. Indeed, altering cells to acquire
                                                                                   more stem-like features is consistent with recent applications of stem-
                                                                                   cell biology to the understanding of cancer. The stem-cell paradigm
             c
                                                                                   might be more than just a means of understanding how malignant
                                                                                   tissue is organized and how cancer might be modified by a specific
                                                                                   microenvironment. It raises the real possibility that a dysfunctional
                                                                                   microenvironmental niche might contribute to the emergence of the
                                                                                   disease (Fig. 4).

                                                                                   Modifying the niche
                                                                                   If the niche is a dynamic structure that has the capacity to be formed
                                                                                   anew, to respond to exogenous signals and to include varying com-
                                                                                   ponents, this raises the question of whether the niche can be a target
                                                                                   for therapeutic manipulation. There are compounds defined for use
                                                                                   in other settings that could be considered for ‘re-purposing’ to affect
Figure 4 | Potential niche contribution to dysplastic cell growth. a, Normal       the niche. Certainly, within the haematopoietic system, the associa-
interactions and occupancy of the niche tightly controls stem-cell number.         tion of the stem cell with bone raises the possibility that compounds
b, Vacancy in the niche might result in ectopic occupancy by another cell          developed for the modification of bone or mineral metabolism might
type. c, Niche signals might impose proliferative or de-differentiative signals,   have a role. Candidates include drugs that affect the osteoblast or
contributing to a disordered state of tissue organization and control.             osteoclast function of inhibiting molecular regulators of stem-cell
                                                                                   interactions with the niche, such as drugs targeting the CaR and OPN
   Although association with microvessels is an intuitively compelling             receptors, or Notch. Experimental evidence has shown that altering
means for a stem cell to be in an environment where system-wide signals            the niche pharmacologically can change stem-cell outcomes, with
can be sampled, the exact components of the vasculature that engage                physiologic impact. For example, the use of parathyroid hormone
stem cells are still unclear. In certain circumstances, such as islet-cell         (PTH) to stimulate the receptor on osteoblasts resulted in an increase
proliferation, the basement membrane may again provide regulatory                  in the number of stem cells under homeostatic conditions. When the
information46. Endothelial cells have been implicated as directly induc-           setting was the physiologic stress of bone-marrow transplantation,
ing neural precursor Notch activation with resultant cell proliferation            dramatic results were noted. The animals receiving PTH had mark-
and differentiation in a manner that vascular smooth muscle cells do               edly improved marrow cellularity and increased rates of survival5.
not47. Pericytes surrounding the endothelium might contribute to stem-             The stem cells do not have PTH receptors, so the effects are indirect
cell regulation, and have been found to be closely associated with mes-            and probably mediated by niche osteoblasts. This effect has been
enchymal stem cells48. Endothelium, pericytes and surrounding smooth               shown to protect resident HS cells from cytotoxic damage during
muscle are all candidate contributors to a perivascular niche for normal           exposure to chemotherapy drugs, to improve harvests of stem cells
stem cells. They might also contribute to the foci of tumour-initiating or         from treated animals and to improve engraftment outcome. Whether
cancer stem cells thought to be responsible for blood-borne metastases.            this paradigm of identifying characteristics of a niche to permit
Recently, it was shown that such a site could be rendered more condu-              rational pharmacologic manipulation can be applied to other stem-
cive to cancer-cell engraftment if modified by intravascular delivery of           cell systems needs to be tested further. However, if demonstrated, this
bone-marrow-derived vascular endothelial growth factor receptor 2                  would offer a novel approach to regenerative medicine.
(VEGFR2)-positive cells49. The idea that stem-cell niches can be modi-
fied or created has experimental support in other systems as well.                 The niche as a target in cancer therapy
   Under conditions of stress, such as fibrosis of the bone-marrow space,          With the recent development of the cancer stem-cell concept, which
extramedullary haematopoiesis develops in humans and mice. Sites such              was first proposed half a century ago but was only empirically shown
as the spleen might re-kindle a developmental vestige (particularly in             by the pioneering work of Dick and others, another dimension of
the mouse, in which the spleen is a haematopoietic organ) or engage                the niche as a ‘druggable’ target is beginning to take shape53. If can-
entirely new sites, such as lymph nodes or soft tissue. These seem to              cer is organized in a manner similar to normal tissue, with a minor
function as regulatory niches for stem cells. Experimentally, niches can           subpopulation of stem cells, an attendant blood supply and a unique
be generated by altered expression of single genes. Stabilized β-catenin           microenvironment, there might be a similar dependence of the stem
expressed under the control of an epidermal-specific promoter resulted             cells on a cancer niche. The possibility of a niche has been shown by
in de novo generation of hair follicles with a presumed attendant stem-            multiple studies indicating distinctive features of non-cancerous cells
cell pool50. Therefore, niches are not static in function or number, and           within a tumour, and by the recent report of a population of bone-
can be created or made to change under specific conditions.                        marrow-derived cells paving the way for subsequent establishment of
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25.   Chen, D. & McKearin, D. Dpp signaling silences bam transcription directly to establish            from the National Institutes of Health, the Burroughs Wellcome Trust, and the
      asymmetric divisions of germline stem cells. Curr. Biol. 13, 1786–1791 (2003).                    Leukemia and Lymphoma Society for supporting this work.
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27.   King, F. J., Szakmary, A., Cox, D. N. & Lin, H. Yb modulates the divisions of both germline       com/reprintsandpermissions. The author declares competing financial interests:
      and somatic stem cells through piwi- and hh-mediated mechanisms in the Drosophila                 details accompany the paper at www.nature.com/nature. Correspondence should be
      ovary. Mol. Cell 7, 497–508 (2001).                                                               addressed to the author (scadden.david@mgh.harvard.edu).




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